Venous thromboembolism (VTE), comprising deep venous thrombosis and pulmonary embolism, is a major contributor to morbidity and mortality in the U.S. We propose a 4-year renewal of the Longitudinal Investigation of Thromboembolism Etiology (LITE), a prospective study of VTE in the Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS) cohorts, comprising 21,680 participants followed for more than two decades. In the previous three project periods, during which 726 VTEs occurred, we successfully identified or clarified, via 55 publications, multiple genetic and non-genetic risk factors for VTE. Especially intriguing GWAS findings relate to the factor XI (F11) and fibrinogen gamma (FGG) regions. We plan to build upon these findings during this continuation, by adding VTE cases, addressing new hypotheses related to risk factors for VTE, and using the information from all project periods to improve understanding of VTE occurrence. Our aims are to: (1) Extend VTE event follow-up in ARIC for six more years, increasing the number of LITE VTE events by 226, to a total of 952. (2) Test the prospective association of incident VTE with novel biomarkers already being measured: Vitamin D markers; measures of liver dysfunction; sickle cell trait; markers of subclinical thyroid dysfunction. (3) Measure plasm levels of factor XI and Y fibrinogen and determine their association with VTE. (4) Conduct a fine mapping study of the F11 and FGG exonic regions in ARIC and CHS whites to identify the likely functional variants underlying our observed associations of these regions with VTE in GWAS. (5) Conduct genetic association analyses in ARIC and CHS whites to identify low frequency variants associated with important plasma intermediate phenotypes (aPTT, von Willebrand factor, FVIII, FXI, and Y fibrinogen), and to evaluate any significant variants for associations wih VTE. This study is designed to provide new information on risk for VTE, with potential implications for prevention and treatment of VTE.